title: Metabolic remodeling in frataxin-deficient yeast is mediated by Cth2 and Adr1.
abstract: Frataxin is a mitochondrial protein involved in iron metabolism whose deficiency in humans causes Friedreich ataxia. We performed transcriptomic and proteomic analyses of conditional Yeast Frataxin Homologue (Yfh1) mutants (tetO7-YFH1) to investigate metabolic remodeling upon Yfh1 depletion. These studies revealed that Yfh1 depletion leads to downregulation of many glucose-repressed genes. Most of them were Adr1 targets, a key transcription factor required for growth in non-fermentable carbon sources. Using a GFP-tagged Adr1, we observed that Yfh1 depletion promotes the export of Adr1 from the nucleus to the cytosol without affecting its protein levels. This effect was also observed upon H2O2 treatment, but not by iron overload/starvation, indicating the presence of a regulatory pathway involved in Adr1 export and inactivation upon stress conditions. We also observed that CTH2, a gene involved in the mRNA degradation of several iron-containing enzymes, was induced upon Yfh1 depletion. Accordingly, decreased levels of aconitase and succinate dehydrogenase were observed. Nevertheless, their levels were maintained in a Δcth2 mutant even in the absence of Yfh1. From these results we can conclude that, in addition to altering iron homeostasis, frataxin depletion involves drastic metabolic remodeling governed by Adr1 and Cth2 that finally leads to downregulation of iron-sulfur proteins and other proteins involved in respiratory metabolism.
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, IRB-Lleida, Universitat de Lleida, Lleida, Spain. Electronic address: ajmoreno@unav.es.
authors.forename: Armando
authors.initials: A
authors.lastname: Moreno-Cermeño
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, IRB-Lleida, Universitat de Lleida, Lleida, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Alsina
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, IRB-Lleida, Universitat de Lleida, Lleida, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cabiscol
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, IRB-Lleida, Universitat de Lleida, Lleida, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Tamarit
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, IRB-Lleida, Universitat de Lleida, Lleida, Spain. Electronic address: joaquim.ros@cmb.udl.cat.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ros
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005800:Genes, Fungal / Q000235:genetics; D054477:Glutaredoxins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051816:Tristetraprolin / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D000426:Alcohol Dehydrogenase; D004268:DNA-Binding Proteins; D004318:Doxycycline; D054477:Glutaredoxins; D049452:Green Fluorescent Proteins; D033862:Iron-Binding Proteins; D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D051816:Tristetraprolin; D000096923:Frataxin; C074682:ADR1 protein, S cerevisiae; C528773:Grx5 protein, S cerevisiae; C091790:TIS11 protein, S cerevisiae
keywords: Friedreich ataxia; Iron; Oxidative stress; Yeast frataxin